By Tom Leslie and Mason Wakley
For the past year the Oxford vaccine has been making headlines as one of our most important tools in the fight against COVID-19. This has been especially true in the last few months, over which the vaccine has been authorised for clinical use in the UK, India, and recently the EU.
Here we talk to Dr Sean Elias, a post-doctoral immunologist and public engagement leader. He works at the Jenner Institute, an Oxford-based institution founded in 2005, which has been at the heart of vaccine development.
The Oxford Scientist: Hi Sean, to start with, would you mind telling us a little bit about yourself and how you came to be talking to us about the Oxford vaccine?
Sean: I joined the Jenner Institute fresh from my undergraduate studies in Biology at the University of Oxford.
My first job was making pre-clinical viral vectored vaccines as part of the institute’s newly founded ‘Viral Vector Core’ facility.
After that, I moved on to working on human clinical trials, before starting my PhD, which was on the topic of B cell immune responses following malaria vaccination. Then, I worked on a number of different diseases, including Ebola virus and non-typhoidal Salmonella (NTS), the latter of which I have designed and run studies for, both here in Oxford and across Africa.
Since the start of the pandemic, I have been involved in a different side of the work, namely supporting our science comms and media.
You mentioned a term that has come up a lot in relation to this particular vaccine, namely ‘viral vectored’ technology. Has this been a significant factor in getting the vaccine to the public as quickly as you did?
The importance of new platform technologies in the development of emergency response vaccines cannot be underplayed. It is undoubtedly one of the major reasons we have managed to develop a Covid-19 vaccine in record time.
Traditional vaccines include attenuated vaccines, containing inactivated pathogens, or subunit vaccines, containing one or more antigens, — which are small parts of the pathogen, such as proteins or sugars,— without the pathogen itself. . The manufacturing process for these traditional vaccines takes time. The process of attenuation, for example, involves the repeated culture of a pathogen in cell lines until they lose the ability to cause disease, which can take months or even years. On top of this, every disease requires different cell lines, conditions, and steps, which complicate the process.
So, to clarify, these newer technologies can bypass some of those limiting steps you require in the more traditional processes?
Yes— in fact, platform technologies, such as the University of Oxford’s Viral Vectored Vaccines, are often referred to as ‘plug and play’ technologies. You develop the vaccine platform in advance (think of it as a game console) and then add in the final component, your vaccine insert of choice, when you need it (think of it as a new game for the existing console). All you need to make this vaccine insert is the genetic sequence of the pathogen or one of its antigens.
As genome sequencing technology has advanced the whole process, it can and, indeed, does occur within a month—from identifying a new disease to making the first vaccine.
Thus, we can rapidly make and test such vaccines without having to optimise every process each time.
Are there other factors, besides technology, that make the Jenner Institute particularly suited to develop this vaccine?
Several factors helped us move so quickly with development and testing.
For one thing, the University has two vaccine research groups: the Jenner Institute and Oxford Vaccine Group, which have worked together a lot in the past. This gave us access to many experienced scientists, research clinicians and support staff, all of whom dropped what they were working on to come together and run the Covid-19 vaccine study.
The phase 1 clinical trial research paper cites over 350 authors, and this number only expanded as we moved forward nationally and internationally.
To perform these trials, we were able to draw on our existing network of clinicians, with national support from teams in Southampton and London, as well as international support from teams in Kenya and South Africa.
It’s important to note that we also had experience on our side. Following the 2014/15 Ebola outbreak, the Jenner Institute set up our Emerging Pathogens group, which aims to respond to diseases with pandemic potential. One of the vaccines this group worked on was Middle Eastern Respiratory Syndrome (MERS), which is another Coronavirus. From this study, we knew that the coronavirus spike protein was safe and immunogenic in our vaccine platform, which gave us great confidence that we would see the same results for a Covid-19 vaccine targeting its spike protein.
And given how important the development of this vaccine has been, have you also seen a lot of support, either from other organisations or the general public?
The public really responded to our call for volunteers.
For the phase 1 study of our vaccine, we had well over the 1000 volunteers that we needed, even by the first day of advertising.
We then needed financial backing in order to move forward with the trials, which is often a limiting step. Even for this vaccine, it took months to secure the funding we needed to run the initial trials and manufacture the early batches. However, this process was significantly faster than usual.
Of great help was also the expedited review of data by regulators. Whilst all the correct processes must still be followed during the pandemic, there was an agreement that data would be submitted to regulators at periodic intervals. This allowed us to stagger the clinical trials so we could start the next phase before the end of the previous one, as long as key milestones had been met.
Speaking of the trials, were there some elements to their design that stand out as particularly important to you?
Based on the populations affected by the disease, it was obvious that we needed to include studies in older adults (55-65, 65+), as well as individuals with underlying health conditions.
In contrast, children were low priority, though we will be going back to them in future. This was also a global disease, so testing it in different international populations was going to be necessary, firstly to ensure safety in different populations with different genetic diversity, but also to build vaccine confidence.
Is this why the trials expanded overseas to Brazil and South Africa?
Yes, in part, but there is also another reason.s. When looking for vaccine efficacy during a pandemic, you require high incidence rates to ensure you can clearly distinguish the protectiveness of the vaccine versus the control group. When we reached this stage of the trial, incidence in the UK was getting quite low; this encouraged us to set up the branches of the trial in both Brazil and South Africa.
In addition, at this point in the study, the cohort we recruited was enriched for front line health care workers. This is considered ethically compassionate during a pandemic, since healthcare workers are more likely to be exposed, but equally their increased likelihood of exposure increases the incidence rate and gives us greater opportunity to test the vaccine’s effectiveness.
How important was the partnership with Astrazeneca, in terms of bringing extra manufacturing power to the table?
The University of Oxford has its own on-site Clinical Biomanufacturing Facility (CBF). They have been producing biological Investigational Medicinal Products (IMPs) for early phase clinical trials for nearly 20 years.
However, the partnership with AstraZeneca and subsequently other vaccine manufacturers, such as the Serum Institute of India, allowed us to manufacture millions rather than hundreds of doses of vaccine. The vaccine made by these partners all comes from the same seed stock produced at the CBF and uses the same manufacturing techniques, which have been ‘tech transferred’ and optimised for increased scalability. This ensures the vaccine is made to the same high standards and the cost is kept down. An important part of our partnerships was ensuring that our vaccine would be supplied at cost during the pandemic to all who need it, particularly those in low- and middle-income countries; manufacturing around the world also helps support this goal.
Looking back on it, how did the development of this vaccine compare to others you’ve worked on, especially in terms of the intensity of the work?
Confining this to lab work, which I am most familiar with, we would normally have 1-2 people working on a clinical study for a single disease, with maybe 4-5 projects running at the same time. A team may process 5-10 blood samples on a busy day, and that may only happen once or twice a week. There will be busy periods but the same team does all the work, including the subsequent experiments on the blood samples. In most cases we can fit that workflow into a regular 9-5y schedule.
In the pandemic all our teams have stopped working on their individual projects to focus on the Covid-19 vaccine. In a single day we may have had between 30-100 blood samples arriving from different sites. Instead of 1 or 2 people doing every job we were all split into a production line, with each person, or team of people, doing a single job. At the busiest periods some of our teams were doing 12-13 hour shifts up to 8 days in a row, working both weekends and nights.
Clearly the people working on this vaccine have made a lot of sacrifices to get the work done. Did you worry much about burnout, or did you manage to find ways to cope with the relentless pace?
Burnout was a real possibility, but luckily, we have a fantastic team which was very supportive of one another. We also had public support— for example one kind donor provided meals for the team for several months at the start of the pandemic. Just knowing you don’t have to bring lunch or have to make dinner after a long shift makes a huge difference to morale. There was also support from the University for those living in shared accommodation, who were moved to empty college rooms to reduce exposure risks, particularly for those who lived with other front-line staff.
What advice would you give to young people, or anyone else, who has become more interested in science this year and wants to pursue it further?
You cannot beat experience in research. If you are an undergraduate considering any form of lab science, my single most important piece of advice is not to rush things and gather experience before moving to the next step. I went into a research assistant position out of undergraduate and had 3 years’ worth of lab experience before starting my PhD. This made it so much easier and more rewarding, and I fully recommend this route, as would many of my colleagues in the vaccine team who have done the same.
So my advice to those budding scientists is this: get in touch with those leading the current efforts, learn from them, listen to them, but also question them. I think the biggest strength of the Oxford University student system is that it teaches students to think originally and outside the box and this is a key part of research.
Image Credit: Emeric Claudiu