UN Talk – Professor Sarah Gilbert
On 13 May Professor Sarah Gilbert gave a short talk and participated in an informal discussion with ambassadors of the United Nations member states, hosted by the UK mission. Here is a summary of her talk.
In the wake of the 2014 Ebola outbreak the WHO R&D Blueprint programme was established to review platform technologies for Diagnostics, Vaccines and Therapeutics, in order to be better prepared for future outbreaks or pandemics. Oxford’s ChAdOx1 vaccine platform technology was presented to this newly formed programme, and it was approved by the WHO.
Following the formation of CEPI, Oxford, in partnership with Janssen vaccines, was funded by CEPI to develop vaccines against the first three outbreak pathogens selected by CEPI: MERS, Nipah and Lassa.
What is the ChAdOx1 vaccine technology?
ChAdOx1 is based on an adenovirus, which is another virus that causes mild upper respiratory tract infections. We have removed some of the adenovirus genes so that when we use it as a vaccine, the adenovirus can’t spread through the body. That makes it very safe, even in people with a weak immune system. But because it is still a live virus, it is good at inducing a strong immune response after vaccination.
There are lots of strains of adenoviruses that infect humans, which means that many people have antibodies against those adenoviruses. These antibodies would interfere with using the human adenoviruses as a vaccine vector. We started from an adenovirus that was isolated from a chimpanzee and doesn’t circulate in human populations, so there is no prior immunity to it. Then we add a gene to encode one of the proteins from the pathogen that we want to vaccinate against – for SARS-CoV-2 we use the spike protein, which covers the surface of the coronavirus.
How have we used the ChAdOx1 vaccine technology previously?
We have already used the ChAdOx1 vaccine technology to produce candidate vaccines against a number of pathogens including flu, chikungunya, Zika and another coronavirus, Middle East Respiratory Syndrome (MERS).
The MERS vaccine completed a phase I clinical trial. It was safe and induced strong immune responses. It was tested in non-human primates who were vaccinated and then exposed to the MERS virus, and the vaccination was protective.
The origin of the ChAdOx1 COVID-19 vaccine
We had started to work on pandemic preparedness with ChAdOx1, to be ready to move as quickly as possible when a new outbreak occurred. We had not been successful in receiving funding for this work, and as a result the work had not progressed very far.
In the first few days of this year there were reports of an outbreak of SARS-like pneumonia in China. I began to follow the reports with interest, and as the situation gradually advanced, I discussed making a vaccine with members of my research team and our collaborators at NIH who have worked with us on preclinical vaccine efficacy studies.
As soon as the virus sequence was released, we started to make the vaccine based on the approach we had used for MERS, using a small amount of flexible funding that was available to me.
The work so far
Since January, the project has developed rapidly, moving into GMP manufacturing, with two vaccine efficacy studies in non-human primates now completed, and two further studies in ferrets underway.
In the UK we have now vaccinated over 1000 people in a phase I clinical trial. Unusually for a phase I study, participants are randomised to receive either the COVID-19 vaccine, or an unrelated vaccine.
During the follow-up period any participant experiencing symptoms of COVID-19 will contact us to be tested. When enough of the participants have tested positive, the statisticians will review the data and tell us the vaccine efficacy.
Vaccinations in the phase I study in healthy adults aged between 18 and 55 were completed on 29 April.
Next steps in the clinical trial
We will shortly begin vaccinating older adults in a phase II study, and also initiate a phase III study with 10,000 participants aged over 18 years.
All of the clinical trials so far are in the UK.
We had hoped to have enough people vaccinated before the outbreak reached a peak, but the virus spread rapidly triggering a lockdown, and rates of infections are now falling. Unless some of the trial participants do become infected, we cannot know that the vaccine is effective.
We are thus focusing on vaccinating healthcare workers as they have the highest rates of virus infections. Further, as measures to ease the lockdown are being introduced, transmission may rise again.
Many discussions are underway but are confidential for now. We need to manufacture more vaccine for the trials, and plan to start trials in more than one country to give ourselves the best chance of determining vaccine efficacy.
Manufacture of the vaccine
In parallel with the clinical trials we are working with a number of contract vaccine manufacturers to get them ready to make large quantities of the vaccine (if it is found to be safe and effective).
Development of Oxford’s vaccine is now funded by the UK government and we have a new partnership with AstraZeneca, to prepare for very large-scale vaccine supply. The contract was recently finalized.
Vision for future collaboration
If Oxford’s vaccine is successful, others’ will be as well. One of the lessons learned from Ebola must be to enable multiple vaccines to be licensed rather than end up with a monopoly.
But it is not likely that ALL candidate vaccines now in development will be effective, and many will require more than one dose.
Vaccine developers should work together to compare immune responses, and assess different vaccine platforms. Technologies which can be manufactured at large scale and low costs should be prioritised, but they also need to be highly effective.
What should the way forward be for future outbreaks and pandemics?
The world needs a small number of pandemic response research institutes. These would have advantages over both biotechs and large pharma companies in being able to respond rapidly, with a range of different technologies available. The institutes need core funding as well as access to flexible funding when needed. Funding for the early stage of pandemic response should not be a bottleneck.
These institutes should be independent but also collaborative, and may be complementary in their skills.
Access to flexible vaccine manufacturing facilities capable of making millions of doses of vaccine will be needed, but this may be achieved through partnerships with contract manufacturing organisations in some cases. Or there could be advance arrangements in place with large companies to take over activities in the event of a new large outbreak.
There must also be connection with many clinical trials sites in many parts of the world, as Oxford has in place, to enable rapid clinical development. In some parts of the world there are delays in ethical or regulatory approvals for trials to be initiated, and there is work to be done on that.
Immunology assays must be shared, or at least results must be able to be compared, with core labs for key samples. One idea would be for each institute to act as a core lab for certain types of assays.
More capacity for preclinical research is also needed.
We did learn some lessons from Ebola, but we were still not sufficiently prepared. Again, clinical trial protocols are still being discussed and whilst funding has been pledged for vaccine purchases, much needs to be done on funding efficacy trials, and getting manufacturing sites ready for large scale manufacture.
Efficacy trials should be conducted with vaccines using well known technologies, that have a high chance of success, can be manufactured at large scale, and will be affordable. We need to vaccinate across the world now and will need many manufacturers to make enough doses to achieve that.