The world’s longest endurance event
The challenge
‘We started the first trial in 2002 and we finished the efficacy trial in 2013.’
Nine years of trials. That was on top of the time taken to develop the thing in the first place. That’s a long time.
Le Mans takes 24 hours. The Marathon des Sables, billed as the toughest footrace on earth, is over in six days. The Vendee Globe round the world yacht race can take 150 or so days. These are all considered defining tests of human endurance.
Vaccine development may not be as physically demanding, but to keep plugging away for twenty years surely requires mental resilience. For Le Mans, the MdS and the Vendee Globe, the finish line is known, fixed; for vaccines, new data may move the finish line at any time. Imagine getting halfway round the world to discover that not only has the end moved two hundred miles further away, but you’re heading in the wrong direction…
So I decided to ask three Oxford scientists with a wealth of vaccine knowledge about what they did and why they kept doing it.
The first was Helen McShane, Professor of Vaccinology, specialist in TB, who began by outlining the vaccine development process.
‘We design and construct vaccines. We then test them in different animal models. When they look good we then move them into early clinical testing. And when they look really good we then move them into testing through my collaborations in science in Africa.’
Put it like that and it sounds quite straightforward. Just along from Professor McShane is Professor Adrian Hill, director of Oxford’s dedicated vaccine research centre, the Jenner Institute. He colours in that outline, drawing on his own experience in malaria vaccine research.
‘From the idea to licensing a vaccine is a very long road. You can divide it into two very large parts. One is pre-clinical — before you start vaccinating people — and the second part is clinical, which is all the clinical trials you would do to go from your first human vaccinee to convincing a regulator that the vaccine was safe and effective. Each of those will take years.
‘In a way it’s easier to describe the clinical development because it happens in three phases. Phase one, which tends to be a safety trial to show that the vaccine doesn’t do any harm. You typically measure some immune responses. Then in phase two you try to get the dose optimised. You figure out how many immunisations you need to give, what the interval between them should be — the immunisation regime — and you test the vaccine in a lot more people and often in different settings. You might in malaria do that in the country of origin of the vaccine, in our case the UK, say in a West African population where there is Malaria, and then you’d go on from adults where you typically test a vaccine first to the group you really want to immunise, which in the case of malaria is young infants. That takes time, because you can’t just one day immunise a lot of adults and the next week immunise babies — you have to age deescalate carefully.
‘And all the time you’re monitoring safety because any serious adverse event that pops up at any stage of the clinical process can flag the end for that vaccine candidate. So that would typically take five or ten years of clinical development — if everything goes well.
A phase one trial is typically maybe half a million pounds, a phase two trial is millions of pounds and a phase three trial is many tens of millions of pounds, so people have to be more and more confident at every stage that this is going to be a real product that will save lives.
‘Of course one of the challenges with public sector vaccine development, where you’re raising money to fund your next clinical trial all the time, is every time you’ve done a trial to persuade the next group of funders or next funding agency that the results are promising enough to justify going forward.
‘So there’s continuous review and unfortunately the amount of money required to keep going gets larger and larger. A phase one trial is typically maybe half a million pounds, a phase two trial is millions of pounds and a phase three trial is many tens of millions of pounds, so people have to be more and more confident at every stage that this is going to be a real product that will save lives.
‘On the pre-clinical side of things, it’s faster but it’s more complex. You have many more decisions to make in early stage research, for example — what antigen you will use in your malaria vaccine — there are thousands. What way you will deliver the antigen? That’s what we call immunogen design — how will you design the vaccine so that you get a strong immune response that will last for a long time? If it doesn’t last for a long time, your vaccine won’t work for very long.
‘Other questions are very relevant, for example are you going to be able to manufacture this vaccine, not just to do a trial but eventually to vaccinate maybe 100 million babies around the world every year to stop them getting malaria. That isn’t going to be possible for every type of vaccine you think of and for some that it’s possible for it will be too expensive, because we can’t sell a malaria vaccine for 100 dollars; it has to be cheaper than that because someone else is going to be paying. So there are lots of considerations, there’s lots of debate. You must test your vaccines in animals, for several reasons: to establish safety, to look at the immune response that’s produced to see if it works in small animals. If it doesn’t you’re probably not going to be supported to go further into human testing. So we have actually more people doing pre-clinical malaria research than we have doing malaria clinical trials.’
Given in such detail, it sounds daunting enough. Yet, Professor McShane adds another detail — a critical one. To trial a candidate vaccine requires volunteers, people willing literally to roll up their sleeves and be injected with a new biological agent, or in the case of the later stages of her MV85A TB vaccine study, willing to volunteer their baby.
‘The first study you do is what’s called a ‘phase one — first in man’ and that is literally the first time anything has been tested in man. Those are very small studies, typically 12–20 subjects. We then test it in other populations that are relevant for TB vaccines, so for example we would look at safety and immunogenicity in what we call latently infected people or people with HIV, who are more likely to get TB. Those trials would also take 12–20 subjects.
‘We would then move to phase 2a studies in the developing world where TB is prevalent. Here the numbers go up a bit so you then vaccinate 50 to 100 subjects. One of the important target populations for a TB vaccine is infants — because they get a lot of TB. If you give a vaccine to an infant the best case scenario is that you give it at the same time as all their other vaccines because then you minimise additional visits to the clinic and you’re more likely to vaccinate more children. To do that you have to make sure the new vaccine you’re adding doesn’t interfere with the existing vaccines, so you do what’s known as a non-interference study. We did one with 300 babies in the Gambia.
‘And then there’s a big jump between those studies and what we call the phase 2b efficacy trials and for those studies you need very big numbers because although there’s a lot of TB in the world, in any population the incidence — new cases per year — is actually quite low. So you need a high incidence population because you need as many new cases as possible — because that’s your measure of efficacy. you’re counting the number of new cases in a given time period in your vaccine arm versus your placebo arm. So in our efficacy trial we had 3000 babies.’
More common diseases might require fewer volunteers than Professor McShane’s 3000, but even then you’ll need hundreds of people to agree to take part. Without enough volunteers, you have no clinical trials; without clinical trials, you have no progress. Yet, not only are there volunteers, some of those in Oxford who take part in early trials choose to return again and again to support research.
What’s exciting about being at Oxford is we can do it and it works.
A mile away is Professor Andrew Pollard, director of the Oxford Vaccine Group, which specialises in paediatric vaccines. He echoes the issue of volunteer recruitment.
‘In trials the delivery is an enormous undertaking because of the cost, the logistics and the regulation and just getting out there to get volunteers in to do very complex experiments with them.
‘What’s exciting about being at Oxford is we can do it and it works. There’s such a good machine and wonderful people you can press a button and do a study like VAST: We import a vaccine from India, give it to volunteers, challenge them a month later with a pathogen that in some parts of the world is killing people, and at the end of it have a readout that helps inform global policy. You can’t really beat that.’
The outcome
Inevitably there are lots of ups and downs along the way.
So that’s the practical challenge. But is it worth it? Does all that work finally pay off?
Not always.
The three researchers seem sanguine about it. Professor McShane wryly notes: ‘Inevitably ‘there are lots of ups and downs along the way.’
‘The first four volunteers we vaccinated with MV85A, we saw enormously strong responses to that vaccine, much more than we were expecting and I still remember the day my postdoc walked round the lab with the results and showed me them and I thought he must have made a mistake. They were twenty times higher than we were expecting the responses to be.’
The reality of day to day doing research is that there is lots of stuff that doesn’t work, which is a bit frustrating.
Professor Pollard calmly tells me that the majority of vaccines in most fields that have been developed don’t even step into phase one, and many of those that do don’t progress much from there:
‘We don’t understand the immune system quite well enough to know why, when it doesn’t work, it doesn’t. The reality of day to day doing research is that there is lots of stuff that doesn’t work, which is a bit frustrating.
‘There is a huge challenge to get to phase I because of the costs of manufacturing a vaccine to the standards required by regulators…..but for those candidates that look promising further development is very much driven by the likely size of the market and the potential for large investment required to get to phase III being recouped.’
I push each of them on this — surely they feel more than slight frustration?
I’ve sat in this chair and just started at a piece of paper which says that vaccine isn’t working at all and that’s a bad experience.
Professor Hill describes a negative result as ‘like losing a football game only worse because this football game has sometimes lasted two or three years — if not more. And you finally get it into the clinic, do an efficacy trial and there’s no efficacy.
‘I’ve sat in this chair and just started at a piece of paper which says that vaccine isn’t working at all and that’s a bad experience.’
Professor McShane describes her experience with MV85A. After the joy of those unexpectedly positive results, the vaccine progressed to that trial in 3000 babies:
‘Eight of us — the eight people who led the trial — pretty much locked ourselves in a hotel room in Cape Town and got the results. None of us had seen the results and we were literally handed a folder with all the results in at 9 o’clock on a Monday morning. And we all sat and looked at the results together and all looked at each other.
‘Five years of an efficacy trial and ten years of vaccine development, to discover that the vaccine, whilst safe, had not improved protection against TB compared to BCG alone. I was enormously disappointed; pleased it was safe, pleased that there was absolutely no evidence that we had done any harm with this vaccine, but clearly it hadn’t worked.’
Adrian Hill describes the first field trial of a vaccine his team did in West Africa in 2001. It was the first time they’d really tested their cellular immunity approach. It showed no significant efficacy.
However, he notes that the study revealed firstly that it was not going to be quick and easy and secondly that they were a long way from getting there and would need to do a lot of optimisation. It was, he realised, going be a long road. The first attempt at a malaria vaccine was produced in 1908 and that we still don’t have a vaccine for the disease.
Look at the mortality data for children and they are less likely to die now than twenty years ago. There are probably many reasons for that but vaccines are part of it.
Yet there are successes. Andrew Pollard points out that half of the vaccines in the UK immunisation schedule have trials from Oxford underpinning their development:
‘You look at the UK immunisations schedule and we’ve more than doubled the number of vaccines we give to children compared with the 90s, which is fantastic for public health. Look at the mortality data for children and they are less likely to die now than twenty years ago. There are probably many reasons for that but vaccines are part of it. There are measurable effects in the population; it’s much more dramatic in the developing world where there are huge reductions in the death rate but there is still a measurable fall in childhood mortality even in this country. I feel quite privileged to have been part of that process.’
The motivation
The motivation is firstly to understand why it didn’t work and secondly to realise that by it not working you have learned something that is usually pretty important.
In all the discussions it is clear that the challenges are significant and the outcomes variable. So why?
With timescales of decades offering only uncertain success, where do they find the strength to keep going? Discover the vaccine for X and you can look back and say it was all worth it. But what keeps you going when it looks like you won’t get there?
The answers I get show that that understanding is too simple: It’s tempting but wrong to look at vaccine development in a binary way — you develop a vaccine and it either works or it doesn’t.
But none of the researchers take that view. Compare these three answers describing the response to trials that have not shown a vaccine to work:
Adrian Hill: ‘The motivation is firstly to understand why it didn’t work and secondly to realise that by it not working you have learned something that is usually pretty important.’
Andrew Pollard: ‘We’re learned something that means we don’t pursue that avenue in the future or we know how to do something that we didn’t know before — we’ve learnt some of the technologies that were needed.’
Helen McShane: ‘It’s my view that we will make progress in this field by iteratively doing trials, getting results, feeding them back, using those results to improve the animal models, improve the immunological markers that we use and improve the design of our next generation vaccines.’
Everything is an opportunity to learn and by learning as much as possible, whatever the headline outcome, it seems to me that researchers can mitigate the blow that comes from that outcome.
Helen McShane’s story of that South African TB trial illustrates that. She described what happened after the initial — disappointing — result.
‘I guess we got to Monday afternoon and it took us a few hours to recover from the disappointment collectively as a group and then we realised that yes, this was disappointing but TB vaccines are a difficult field because we don’t have a correlate, we don’t know which — if any — of the animal models predict human efficacy — the only way we can test if a vaccine is going to work is to do these trials.
‘I think we were all and are all utterly committed to learning as much as we can from this study — and my lab has just finished conducting an enormous correlate analysis on the blood samples taken from all of those babies to try to find out more about the immune response we should try to induce — so that we can move on and design the next vaccine. You have to just carry on — TB remains a very important cause of death and disease throughout the world.
‘Even in that first week when we got that efficacy trial result I was starting to think well we could do this instead. That’s the joy of science really — that there are always other things to try. We will have five or six projects ongoing; the nature of science is that some of those will work and some those won’t work but as long as they don’t all bomb at once then there’s always something to keep you going. There’s always another idea, there’s always something you can do to make it better. I guess it’s just got me hooked.’
Future vaccines could be a single shot that protects you for life.
That excitement — the sense of enquiry, discovery and potential — is also clear when I speak to Andrew Pollard. He tells me how technology, such as gene sequencing, means that we can understand much more about both the pathogens and the immune response to them.
‘It’s almost that we’re getting to the top of a hill — we’re not quite sure what’s over the top of the hill in the way that we use technology to understand immune responses. We’re getting vast amount of data from genomes, transcriptomes and so on. It feels like we’re developing this enormous new multi-parameter dataset that will help us understand the immune system and how complex it is.
‘That’s exciting although our problem is processing that amount of data to turn it into something useful but it feels like when we get over that it is just going to the transform the way we use that information to design the next generation of vaccines that hopefully will be safer — we’ll know what gives you a sore arm or a fever and we’ll stop those things from happening — and perhaps one day we will also be able to design out risks for developing rare serious side effects. So if you can identify all those aspects and at the same time find what makes really good immune responses that protect you, future vaccines could be a single shot that protects you for life.’
It’s the people things that are the bit that matter the most.
Do not be fooled into thinking that this is the scientific excitement of academics divorced from reality. Professor McShane walks across the road from her office each week, to where Dr McShane runs an HIV clinic.
‘It’s very grounding because I go from this wonderful academic stimulating environment where every day I have fascinating conversations. I have this wonderful team of people and this wonderful team of collaborators that I have really interesting conversations with — so then I just go and get my feet put back on the ground and see real life at its rawest.’
When I ask Professor Pollard about highs and lows, I do so expecting him to talk about moments in research.
‘It’s the people stuff which is the best and the worst. The science is what gets you out of bed in the morning. The worst things are some of the personal tragedies that happen to the staff that you work with.
‘It’s not the science, which is par for the course — you know, your ups and downs: you get the excitement of the paper coming out or the discovery of something, your work being used to inform policy decisions. For me, it’s the student getting their DPhil and launching on their career or sometimes leaving Oxford and getting their first job after they’ve finished. So it’s the people things that are the bit that matter the most.’
It seems vaccine research has two drivers: Science and humanity. There’s no doubt that all three experienced researchers are still excited by the journey of discovery they are on. However, there’s also no doubt that they are motivated by the desire to do something good for people. In the end, it’s something Helen McShane said that sticks most in the mind, part of her answer when asked how she kept going.
It’s too important not to.
The University
If we’re ever going to crack these tough vaccines like cancer, like HIV, like TB, you need a substantial effort in major research universities.
I ask Adrian Hill whether it takes a certain type of person to do vaccinology.
‘I think we are self-selected. Just to raise money is tough going — success rates are low. I think you can see the pathway by which something should work and feel you can make it work.’
That determination to make it work is how in the last sixteen years Oxford has become a key centre for vaccine research. In 1999, when Adrian Hill began trialling his first malaria vaccine Oxford had no other vaccine makers, although there was a small unit testing vaccines made by other people. However, Professor Hill was supported by long-time Oxford partner The Wellcome Trust.
In many ways that reflects a wider development. Despite it being 220 years since Edward Jenner’s first vaccination, vaccinology has only been seen as a research discipline in its own right in the last twenty to thirty years.
It used to be that companies made vaccines and some universities did trials. That model has changed, driven by the increasing complexity of vaccine development when faced with diseases like malaria and HIV. The intensive, prolonged programmes of research required are very unlikely to get approval from investors. As Adrian Hill puts it:
‘If we’re ever going to crack these tough vaccines like cancer, like HIV, like TB, you need a substantial effort in major research universities.’
At the same time, major funders like the Wellcome Trust and the Gates Foundation have focussed on global inequality and the paradox that science can put men on the moon yet not stop babies dying of common infectious diseases on earth. In the last fifteen years this large scale funding for global health has focussed on vaccination because of its cost effectiveness as a healthcare intervention.
This has led to a realisation that vaccinology is a form of translational research that you can carry out in a university from fundamental science through manufacturing into clinical development and even to late stage clinical trials. All of that can be done at Oxford, from the structural testing of possible antigens to clinical trials using the University’s network of overseas units.
In 2005, an agreement saw the Jenner Institute relocate to Oxford, with a statement of intent that it would be judged on its ability to develop and test new vaccine candidates. Meanwhile, the Oxford Vaccine Group has continued to develop its speciality in paediatric and maternal vaccines.
The University provides the core facilities that allow researchers to pursue vaccines for diseases from RSV to Cancer. They even include an in-house clinical manufacturing facility where batches of trial vaccines can be produced and where processes can be developed to ensure that an effective vaccine can be made in a way that will scale up to meet global demand.
It is not just physical facilities however. Oxford’s research governance and oversight of clinical trials ensures that clinical research is of a quality that protects patients, reassures regulators and delivers robust results.
Beyond these practicalities, the development has means that there is a critical mass of scientists who can exchange ideas and learn from each other. Little wonder that some of the best researchers wanting to get into the field want to do that at Oxford.
When they do, they will doubtless face similar situations to Professors Hill, McShane and Pollard — unexpectedly good and bad results, breakthroughs and apparent dead ends, days when progress seems swift and days when it seems reversed.
Their endurance events will build on those that have gone before and those going on now. They will learn from each other, draw support from each other and assist each other. Finish lines will move, sometimes closer, sometimes further away. New discoveries will offer more routes, new data will offer deeper understanding. They will keep going until — eventually — there will be vaccines for TB, for Malaria, for RSV and even for Cancer.
Credits
Written by Tom Calver
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