UK experts have been giving updates on progress towards a COVID-19 vaccine in an online event hosted by the Science Media Centre.
The Jenner Institute and Oxford Vaccine Group clinical teams are developing a ChAdOx1 nCoV-19 vaccine based on an adenovirus vaccine vector and the SARS-CoV-2 spike protein.
Prof Sarah Gilbert, lead researcher of the vaccine development programme, and professor of vaccinology, University of Oxford, told the Lancet she hopes to have vaccinated 500 volunteers by mid-May.
At yesterday’s Downing Street briefing Business Secretary Alok Sharma announced a vaccines task force. It will be formed from Government, industry, academia, and regulators. “The task force will coordinate with regulators to facilitate trials, which are both rapid and well supervised, and it will work with industry in the UK, and internationally, so we’re in a position to manufacture vaccines at scale,” he said.
Chief Scientific Adviser Sir Patrick Vallance said: “Just to put some realism on vaccine development, that each single project does not have a high probability of success. So although everyone goes out with great enthusiasm, and we hope they work, it’s never the case that you know you’ve got a vaccine that’s going to work.”
Prof Gilbert and colleagues have been answering questions.
How does the lockdown affect clinical trials?
Prof Andrew Pollard, chief investigator on the study, and professor of paediatric infection and immunity, University of Oxford: “If there’s no transmission of the virus and no cases, it really makes it very challenging to be able to test whether the vaccine works in preventing the cases.
“I think because we’re very close to getting underway, and there is still some transmission there’s a reasonable chance that we’ll be able to pick up the efficacy of the vaccine over the next couple of months. But it’s definitely a question that needs to be addressed within these trials.
“I think the main issue is, if there is not very much transmission, then it may take much longer to be able to demonstrate that the vaccine works in the wild, so to speak.”
During lockdown would you target key workers or areas where the curve is rising?
Prof Pollard said that was something “we’ve been puzzling over, over the last weeks”. He continued: “We need to make sure that we’re identifying individuals who are more likely to be exposed to virus, that would be very important going forwards. So for example, studies involving healthcare workers might be one route to do that. We haven’t made that a specific strategy at the moment. That’s certainly a possibility.
“We are indeed already working with partners in other parts of the world to go through the regulatory and ethical processes to be able to set up trials elsewhere, particularly focusing on Africa, where there’s clearly a great need, potentially, in the future to have vaccine available.”
Are challenge trials being considered?
“This is where volunteers are deliberately infected with coronavirus after they’ve been vaccinated.”
He said: “There have historically been some challenge trials with coronavirus done in the past but those were the coronaviruses that caused the common cold, rather than the ones which caused the pandemic.
“Of course the risk of a challenge trial would be if you were to challenge a volunteer with the virus, and you had the dose wrong and it led to very severe disease. And that’s going to make it quite difficult to initiate those sorts of studies, until we have some treatments that could be available if things went wrong in one of those trials.
“So I think at the moment, there’s a lot of interest in this and people thinking about how it could be undertaken, because it would really accelerate vaccine development, but there are some major hurdles to make sure the safety of the volunteers in that setting.”
What stopped you running a challenge trial alongside a normal phase 3 trial?
Prof Adrian Hill, director of the Jenner Institute, University of Oxford: “The fact that there is no challenge model for this disease established, or even initiated, anywhere in humans. At the moment it’s an idea that’s being discussed. The obvious problem with a challenge model is that you need to ensure that giving somebody the virus is safe.
“We haven’t done that. It’s difficult to do that very, very quickly, because you have to do it carefully.
“It’s not at all clear that if you can do a real efficacy trial acting against natural infection you need a challenge model that takes longer to set up.
“But if we, for any reason, do not succeed in finding a vaccine while there’s a lot of this virus around, and then it mainly disappears, I’m sure there will be efforts to develop a challenge model, ideally … once there’s a drug available to treat the infection should you give too high a dose to any individual.”
Do you expect vaccines to work better in some groups than others?
Prof Pollard: “For most vaccines the immune system in older adults, particularly those over 70, doesn’t make such good responses.
“That’s one of the things we need to evaluate in our trials, is how well does this vaccine work in that age group?
“The way around that is if you have poorer responses you can give additional doses of the vaccine to try to improve responses.
“If we did see weaker responses in older adults we also have in our plan that we would look at giving additional doses in that age group to try and improve the immune response.”
Prof Sarah Gilbert: “With other vaccines that we’ve developed, particularly flu vaccines, we have tested them in older people going up to people in their 80s. And we do see that the immune response is a little bit lower, but not really very much lower.
“And so as we do the clinical trials, we’re going to be trying to work out how strong the immune response needs to be to protect people and compare the response in adults up to 55, and then up to 70, and then over 70 and look at the differences.
“It’s not that we don’t expect to see anything at all in the older adults but it’s just that it’s likely to be somewhat less and then we’ll have to try and work out if that’s good enough to give full protection. And if not… we can think of giving an extra dose which is likely then to improve it.
“So it’s not that it’s going to work in young people and not at all in older people it’s a bit more subtle than that.”
How much investment is at risk if the 1m vaccine doses planned for September don’t work?
Prof Hill: “Of course the amount of money you need depends on how ambitious you are in having huge amounts, or just large amounts, of vaccine available.
“Other groups are doing this as well, we think ours is probably the most ambitious scale-up programme that there is, at the moment. I guess that reflects to a degree our confidence that this vaccine probably could work and therefore the doses will be needed.”
He added: “If we thought the risk was low, or that the likelihood of success was low, we’d probably go to one manufacturer and have a small number of doses ready. We think that’s unlikely. We think this vaccine has as good a chance, maybe a better chance, than any of the others, and there are lots around - this will be the fourth in the clinic.
“There are other groups doing similar sorts of technologies with adenovirus factors, but not with the chimpanzee adenovirus factor, which is better in several ways, and relatively efficient to manufacture.
“So, one of the big attractions here is that we have a process that was recently developed in the University which gives a higher yield. So the amount of money you need to invest to get to 1m doses is less if your productivity in vitro is five times better.
How much money is involved?
“It’s £10s of millions not millions at the moment.”
Will people need top up vaccinations?
Prof Pollard: “Based on our experience with other vaccines using this platform, it’s unlikely they would need another dose soon.
“I think part of the information will depend on which population we’re studying. As I mentioned before in older adults, it’s certainly possible that the immune responses could be weaker. But in younger adults and certainly with other similar vaccines, for example, there’s an Ebola vaccine, which has been very widely used, using a similar technology, the antibody responses are very strong even a year and more later.
“So I think it’s very unlikely that further doses [would be] needed very quickly, but we will be monitoring all of that as part of the clinical trials that are being undertaken.”
Will the vaccine be produced in the UK?
Prof Hill: “The answer is yes to manufacturing in Britain.”
If it’s being manufactured in the UK does it mean those doses are used in the UK?
“It’s not as simple as that. We’re very concerned that no one country tries to own all of the vaccine because it’s going to be needed internationally.
“That has yet to be sorted out. It links to the funding question: who has funded the vaccine development of the particular batch that is being made?
“We’re not quite at that stage yet, but I do want to emphasise that we’re not trying to supply just one country or even one territory, we want to be able to use the vaccine where it’s needed most. Clearly today that’s in Europe and in North America, but in 3 or 4 months time that might all change, in the way that the pandemic disappeared in China. Africa is looking worrying it might be that a lot of vaccine is needed in low-income countries and we want to be able to provide for that eventuality as well.”
How will everyone in the world get an equal chance of getting the vaccine at the same time?
Prof Hill: There are extensive discussions going on at different levels, about that. One of the organisations that has been particularly active in trying to steer that is the Coalition for Epidemic Preparedness Innovations (CEPI).
“They have been one of the funders for this programme. They are interested in allocation mechanisms that would try and bring together different manufacturers, different groups, assuming that multiple vaccines are shown to work, and having a scheme whereby one can ensure the vaccine is provided first where it’s needed most.
“And it’s unlikely we’re going to have 7 billion doses available very very quickly, so there has to be some prioritisation.”
What sort of antibodies will you be able to check for some months after people have been vaccinated?
Dr Teresa Lambe, associate professor & Jenner Investigator, The Jenner Institute, University of Oxford: “We don’t have a reliable antibody test yet, but we’re working hard on getting that established in our lab, and I’m fully confident that we will be able to look at the immune responses months after vaccination.
“We’ve done this before with emerging and outbreak pathogens, during Ebola, and I’m sure we’ll be able to do it again. We’ve got some really great collaborators who are helping us with this as well.”
Prof Hill: “We are interested in cellular immunity as well as antibodies. There’s evidence from Sarah [Prof Gilbert]’s work on a MERS vaccine that cellular immunity is potentially very important in protecting against coronaviruses. That may well be the case here as well, which is one of the reasons we’ve chosen to use a vaccine technology which is… very good for inducing cellular immunity as well as antibodies.”
Prof Gilbert: “We will be doing these antibody assays in our lab in the way that we always do in the clinical trials. It’s not high throughput. It’s very labour- intensive work. It’s great for doing clinical trials, it’s not really appropriate technology to roll out to serology testing of the whole country.”
How many vaccine doses could be ready by Christmas?
Prof Hill: “Best case scenario, I guess you might have hundreds of millions by the end of the year, but I’m not promising that. Nobody can promise that, but that would not be an unreasonable target, particularly given the manufacturing team that are working on this.”
Is there a drawback with RNA vaccines that, like cancer immunotherapies, may not work in all patients?
Prof Gilbert: The RNA vaccines, they’re really unproven. But there’s been a lot of interest in them because, unlike some other vaccines, such as the VSV [vesicular stomatitis virus-based] vaccines, there is now a VSV Ebola vaccine. That turned out to be really difficult to manufacture in large amounts. You can make it in small amounts for clinical trials, but when you want to make lots of it to use in large outbreaks it’s really difficult to make a lot and have enough of it ready.
“So that was identified as a bottleneck and it’s a really important bottleneck.
“It’s one that doesn’t exist for our adenovirus effective vaccines because as we’ve been talking about we can go to the millions, tens of millions, and hundreds of millions of dose scale per manufacturer per year.”
She continued: “But one advantage of the RNA vaccines is that you can also make them in very large quantities, and fairly quickly. They’re quite simple things to produce. The part that’s missing with the RNA vaccines is knowing how good they are at inducing immune responses in humans and there’s really very little data to go on with that.”
When do you anticipate delivering the first dose of the vaccine candidate to a trial volunteer?
Prof Hill: “We’ll have to wait until Cath [Dr Catherine Green, associate professor, and head of Clinical BioManufacturing Facility, Nuffield Department of Medicine, University of Oxford] has finished with the last bits of testing of the manufacturing before we can be absolutely sure on the date. But it should be within the next week or so.”
Are you confident the virus will be able to cope with virus mutations?
Prof Gilbert: “With our MERS vaccine trial, which is another coronavirus, and again we use the spike protein of the coronavirus in the vaccine, spiked proteins are quite a large protein and we’re measuring immune responses against it.
“And we took serum from the volunteers who had been vaccinated, and we tested its ability to neutralise MERS viruses that had been isolated from different years, different parts of the world, and from humans and camels.
“We looked for the most divergent MERS coronaviruses out there that we could find across the world, and the serum from the volunteers neutralised all of them.
“Yes, there were some changes, but the vaccine produced neutralising antibodies that neutralised all of those different versions. The diversity of coronaviruses within a particular isolate, a particular strain, doesn’t seem to be anything like as high as you get with flu vaccines.”
You’ve talked about being 80% confident the vaccine will work, what about the 20% unknown?
Prof Gilbert: “There’s always an unknown. We can never be certain these vaccines are going to work. Personally, I have a high degree of confidence. This is my view, because I’ve worked with this technology a lot. And I’ve worked on the MERS vaccine trials, and I’ve seen what that can do.
“I think it has a very strong chance of working. So that’s what that’s based on.”
But manufacturing would start at risk?
Prof Hill: “Yes. If the vaccine doesn’t work and you have a million doses sitting there, the money has been wasted.”
What’s the risk of immune enhancement with the vaccine making a subsequent infection worse?
Prof Pollard: “One of the bits of work that’s done before starting studies in humans is to do animal studies with the vaccine beforehand specifically to address that question.
“That has been done with several of the vaccines already in development. That will give I think increasing confidence about the safety of these approaches.
“When we then start doing these clinical trials, we do discuss the potential for immune enhancement of some sort happening in the clinical trials with all volunteers, because it is an unknown.
“But the characteristics of the vaccine that is being developed here should not drive towards the type of immune responses which cause problems.
“Clearly we have to monitor for it, make sure our volunteers are properly informed about it, but all of the possible risk mitigation is done before we go into the clinical trials.”
When would the vaccine be ready for the general population?
Prof Hill: “Once you’ve shown efficacy in your clinical trial, you discuss with regulators what the timing would be for getting approval to use it essentially as an emergency use vaccine.
“This would not be final commercial licensure which will take much longer.
“The University of Oxford has a lot of experience with Ebola vaccines; we were involved with four of these that were tested back in 2014/2015. The one that actually worked in West Africa, took until quarter four of last year to be finally licenced, but of course it was used to help end the epidemic in West Africa, and has been extensively used in the Congo recently, before that final licensure.
“What we’re really talking about is how quickly we could get an emergency use approval from the relevant regulator. And that’s theoretically possible in a matter of about 6 weeks [from demonstrating efficacy and safety], but we just don’t know for this vaccine. All this work has been done unusually quickly. So we need to keep that discussion going with regulators, who so far have been very positive about this.”
What percentage of the population would need to be vaccinated to achieve herd immunity and interrupt transmission?
Prof Pollard: “We don’t know the answer to that question yet for this virus… it’s likely to be a reasonably high percentage in order to do that.”
Prof Sarah Gilbert: The MERS vaccine development was funded by NIHR and CEPI. I am a founder and board member of Vaccitech, which holds the rights for commercial development of the ChAdOx1 MERS vaccine whereas the University of Oxford retains the right to develop the vaccine for public health use.
Initial seed stock development of ChAdOx1 nCoV-19 was funded by EPSRC via VaxHub. Further funding for process development was awarded by CEPI, and for GMP manufacture and the first clinical trial by UKRI. Under the founding agreement for Vaccitech from 2016, the company has non-exclusive rights to the vaccine.
Prof Andrew Pollard is chair of the UK Department of Health and Social Care’s (DHSC) Joint Committee on Vaccination and Immunisation (JCVI) and is a member of the World Health Organization’s (WHO) Strategic Advisory Group of Experts.
Prof Adrian Hill is a co-founder of Vaccitech Ltd which has non-exclusive rights to the ChAdOx1 vector platform and to certain coronavirus vaccines.
Prof Catherine Green is paid by the University of Oxford and Exeter College Oxford. I am on the Scientific Advisory Board of Duke Vaccine Centre. My research teams receive grant income from the Wellcome Trust, EPSRC and UKRI.
Dr Teresa Lambe: “I have received grant funding to develop a COVID vaccine as a Co-I from UKRI (Sarah Gilbert is the PI). I have done limited consultancy work on influenza vaccines and vaccines against shingles.