Rapid development map for the ChAdOx1 nCoV vaccine (AZD 1222)
This case study of a rapid human vaccine development map illustrates how the timeframe for the development and licencing of a new human vaccine can be expedited in the face of a pandemic threat. It captures the lessons learnt from the Oxford-AstraZeneca COVID-19 vaccine development programme, through feedback from the teams that developed this.
List View of process
- Pre-clinical Discovery and Vaccine Platform Development.
- Pre-clinical Discovery - Sequence of new pathogen. Available 10th Jan 20. Day 0.
- Vector vaccine design. 27th Jan 20. Day 17.
- Manufacturing - Vaccine Seed production. 28th Jan 20.
- Manufacturing - Production of GMP vaccine. 17th Mar 20 to 22nd April.
- Pre-clinical development, including safety in small animals, livestock and primates.
- Phase 1 clinical trials. Start 23rd April 20. 104 days. Completed by 21st May 20. 18th Jul 20 immune response data available.
- Phase 2 clinical trials. 22nd May 20 recruitment begins.
- Phase 3 clinical trials. 22nd May 20 recruitment begins. Result 23rd Nov 20. 312 days.
- Manufacturing scale-up. AstraZeneca 30th April 20. Starts 111 days.
- Large scale GMP batch production.
- Regulatory review.
- Regulatory approval. Emergency approval 30th Dec 20. 349 days.
- First dose of approved vaccine administered. 4th Jan 21. 359 days.
In order to respond to pandemic disease threats, there is a growing need for new and improved vaccine technology platforms that offer the opportunity for rapid product and process development, convenience of manufacture and ease of administration. In the case of COVID-19, the Oxford team had already identified the vaccine target from previous work on coronaviruses and had the vaccine delivery platform ready as a result of years of scientific and engineering research, including research funded through the UK Vaccine Network.
The COVID-19 vaccine developed by the Jenner Institute in Oxford, UK was based on a platform technology that had been in development for over eight years. Starting from a sample of a chimpanzee adenovirus known as ‘Y25’ provided by Wadell, a Jenner graduate student (Matthew Dicks, working with senior virologist Matthew Cottingham) created and performed early testing of the ‘ChAdOx1’ vector in 2012 (Dicks et al., 2012).
ChAdOx1 differed from Y25 in two key ways. The genes needed for the virus to multiply in human cells were completely deleted. One of the Y25 virus’ ‘non-structural’ genes was exchanged for one from a human adenovirus, which would make the virus easier to manufacture.
Most importantly for development of the COVID-19 vaccine, this vector had also been used to develop another Coronavirus vaccine candidate against Middle East Respiratory Syndrome (MERS), with research on this starting in 2017 and progressing to a successful Phase 1b trial in 2019 to early 2020. (Alharbi et al, 2017, Bosaeed et al. 2022).
After the emergence of COVID-19 in November 2019, it was on 12th January 2020 that China publicly shared the genetic sequence of the SARS-CoV-2 virus, the causative agent of COVID-19 (Chan, 2020). This was two months prior to the announcement by the World Health Organization that the outbreak of COVID-19 had become a pandemic. The early sharing of the genetic sequence was an essential pre-requisite for the development on novel vaccine approaches based on the delivery of the immunogenic ‘spike’ protein of the virus.
Using the previously well characterised ChAdOx1 vaccine vector, promoter and terminator sequences, the final design of the vaccine to express the selected antigen included the choice of whether to add an N-terminal leader sequence, whether to express the complete antigen or only part of it, and selection of an optimised DNA sequence to express the desired protein sequence (Watanabe et al.). For the Oxford-AstraZeneca COVID-19 vaccine, the vector expresses a full-length codon-optimized SARS-CoV-2 spike protein (MN908947) with a leader sequence of tissue plasminogen activator (tPA).
The steps for pre-clinical development and testing involve using a research grade vaccine preparation to confirm immunogenicity in animal models, and ideally demonstrate absence of vaccine associated pathology on exposure of vaccinated animals to the pathogen, plus evidence of vaccine efficacy. For the Oxford-AstraZeneca COVID-19 vaccine, the initial animal models used were mice and rhesus macaques.
The Clinical Biomanufacturing Facility at the University of Oxford started making adenovirus vectored vaccines in 2007 for Professor Adrian Hill's malaria vaccine projects. Vaccines using the ChAdOx1 platform had been made and released to trial by the Clinical Biomanufacturing Facility since 2012, targeting many important diseases including Influenza, TB, Meningitis, MERS, Zika, Rabies and Plague. This extensive experience in manufacturing vaccines using this platform, allowed GMP-grade manufacturing of the investigational vaccine to start earlier. From the point which the genome sequence of the SARS-CoV-2 virus was released, it took approximately a month for the designed sequence to be synthesised and cloned into the vaccine vector backbone by the team at the Jenner Institute in Oxford. The DNA material was then transferred to the Clinical Biomanufacturing Facility, headed by Dr Catherine Green, who had developed new, rapid methods to make and test viral seed stocks. This enabled fast progression to GMP manufacture and eventual release of clinical material to the first-in-human trial in Oxford 65 days after DNA receipt, on 23rd April 2020.
In order to be able to start clinical trials within a very short timeframe, the Oxford COVID-19 trials team, led by Professor Andy Pollard (Director of the Oxford Vaccine Group), started developing the clinical protocol, organising ethical and regulatory submissions, trial logistics, identifying trial sites, and starting recruitment of the volunteer participants, throughout March and April 2020. This involved close liaison with the UK Medicines & Healthcare products Regulatory Agency (MHRA). As the first volunteers were immunised, the huge logistical operation continued throughout the Spring as the plans for large scale trials across the UK and worldwide were developed.
The purpose of Phase I trials is to test vaccine reactogenicity and immunogenicity in young healthy adults. For the Oxford-AstraZeneca COVID-19 vaccine, a very large Phase I trial was initiated while combined phase II&III clinical trials were being developed. The phase I UK trial involved 1000 participants commencing on 23rd April 2020.
Phase II trials expand the population tested to larger numbers and a wider range of ages, again determining vaccine reactogenicity and immunogenicity. In a Phase III trials a much larger number of individuals is included with a 1:1 randomisation of vaccine to control, and vaccine efficacy is determined once the number of confirmed infections in the trial reaches a pre-defined limit.
The UK Phase II started in May 2020 and phase III in June 2020. The UK initiation of the phase III trial was shortly followed in June 2020 by Phase III trials in Brazil and Phase I/III trials in South Africa, and later by heterologous prime-boost studies with other vaccines. For the Oxford-AstraZeneca COVID-19 vaccine development, the Phase I/II/III clinical trials were combined for regulatory submissions with a total number of 24,422 volunteers included.
In the early stages of developing the new COVID-19 vaccine the Jenner team could not know whether the vaccine would work. However, in order to have vaccine available for larger scale trials, and indeed for deployment within 2020 should the trials be successful, it was necessary to in parallel develop methods to make a lot more vaccine. This was led by Dr Sandy Douglas who was driving the initial process development and scale up and tech transfer to external industry partners, including eventually AstraZeneca’s network, to enable manufacturing first using 50 litre bioreactors, then to 2000 litre scale, to produce the billions of doses that were eventually deployed across the globe. One hundred million doses of the Oxford-AstraZeneca COVID-19 vaccine were procured by the UK Vaccines Taskforce for distribution the UK and its overseas territories.
In the case of the COVID-19 vaccine licencing the MHRA conducted a rolling review of the clinical data from September 2020 so that it could be assessed shortly after it became available, whilst ensuring rigorous, detailed scientific review. This had a significant impact on the overall development timeline.
Of particular importance was the vaccine safety data. The timeline for safety data is 28 days in all cases including an emergency situation, and a median of two months for Serious Adverse Events (SAEs) and adverse event of special interest (AESIs). This proved to be the rate limiting step for the initial COVID-19 vaccine evaluations. As a result, the MHRA could not approve new vaccines as soon as the efficacy analysis was done. However, this needed to be balanced against the imperative for safety data and ensuring public confidence in the safety of the vaccine.
The Oxford-AstraZeneca COVID-19 vaccine was approved for use in human clinical trials by the MHRA on 30th December 2020, and the first vaccination outside of a trial was administered on 4 January 2021.The decision to approve the supply of this vaccine was taken under Regulation 174 of the Human Medicine Regulations 2012, which enables rapid temporary regulatory approvals to address significant public health issues such as a pandemic.
In the future, it is believed that the MHRA would also look at an accelerated rolling review in the case of a pandemic situation. However, the availability of stability data would be a challenge for any accelerated timetable since real time data is required and generally a minimum product shelf-life of 6-12 months should be provided. Guidelines for this rolling review process are available from the GOV.UK website.
The Oxford-AstraZeneca COVID-19 vaccine is no longer in production owing to the subsidence of the COVID-19 pandemic and the availability of updated vaccines. AstraZeneca withdrew its marketing authorizations for the vaccine from the European market on 27 March 2024, and worldwide by 7 May 2024.
However, work continues with application of the ChAdOx1 platform to other infectious diseases, while also looking to approve manufacturing speed and scale. Learnings could be leveraged to inform vaccine design for related viruses, giving the world a head start in rapidly responding to future outbreaks in as little at 100 days.